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Authors: Gyongyi Szabo, Mack Mitchell, Craig J. McClain, Srinivasan Dasarathy, Bruce Barton, Arthur J. McCullough, Laura E. Nagy, Aimee Kroll‐Desrosiers, David Tornai, Hyesung Alice Min, Svetlana Radaeva, Lisa Casey, Jennifer Cuthbert
Journal: Hepatology (2022)

Gyongyi Szabo, Mack Mitchell, Craig J McClain, and Srinivasan Dasarathy contributed equally to this work. We appreciate the comments from Singh, Mishra, and Jindal, as well as from Gupta, Nath, and Anand. We were also disappointed that the anakinra + pentoxifylline (PTX) + zinc therapy was not superior to corticosteroids in the treatment of severe alcohol‐associated hepatitis (AH). We do believe that our approach of targeting several mechanisms of liver injury may prove effective in future studies using other agents. Trials that began before initiation of the defeat alcoholic steatohepatitis (DASH) trial, including steroids or pentoxifylline for alcoholic hepatitis (STOPAH), did not use Lille criteria as a stopping rule. Rates of infections in the DASH trial were similar to those reported in previous trials. We agree that future trials should employ Lille stopping criteria. The DASH trial was designed over a decade ago, before publication of the STOPAH trial and others that showed a lack of efficacy for PTX.[1] We have previously postulated that some of the variability in the reported effectiveness of PTX might be due to compliance issues (PTX causes gastrointesstinal distress, and t.i.d. dosing (three times a day) is especially challenging in subjects with alcohol use disorder). We also agree that evaluating cytokine profiles and biomarkers of gut permeability would be interesting, and these studies are underway. Anakinra was safe in our trial, and other studies have also reported its safety in peri‐ and postoperative treatment in patients undergoing renal transplantation. Most recently, the European Medicines Agency recently approved anakinra in acute COVID‐19 infection. We, however, do not agree that a liver biopsy is necessary because a patient is overweight or obese. Our patients met the clinical and biochemical criteria for severe AH in the article referenced that we coauthored.[2] Liver biopsies confirmed the presence of steatohepatitis in 92% of patients in the STOPAH trial that used similar inclusion/exclusion criteria to the present DASH trial.[1] Furthermore, liver histology cannot reliably distinguish alcohol‐ from obesity‐related liver disease. We suggest novel biomarkers such as K‐18, which was diagnostic, prognostic, and theragnostic in the STOPAH trial, may function better at diagnosing severe AH than invasive liver biopsies in the future.[3] Moreover, over two thirds of Americans are overweight or obese and, by the authors' logic, would require liver biopsy even when consuming an average of more than 10 standard drinks/day, as in our study. The authors state that obese patients are known to respond poorly to corticosteroids, yet the article they cite relates to a relatively small study from India of only men, with responders having a Body Mass Index of 23.9 and nonresponders having a BMI of 26.5 (not significantly different and not obese).[4] Furthermore, patients in South Asia, including India, have a high rate of NASH in the absence of obesity. The suggestion that 10%–20% of patients may have other diseases is somewhat misleading; the biopsy is more likely to show a different stage of the same disease process (e.g., alcohol‐associated cirrhosis without AH). We also agree that malnutrition is widespread and important in AH. The protocol for nutrition therapy for our patient published by one of the authors (CJM) in the most recent Schiff's Diseases of the Liver[5] is widely used by hepatologists in the United States. Despite the term malnutrition referring to a combination of phenotype and metabolic perturbations, there are multiple publications that demonstrate the contribution of sarcopenia to outcomes in ALD. We are further investigating the impact of nutritional status on outcome in these patients. We also recognize that anakinra in its current formulation is more expensive than steroids; however, patients ineligible for steroid treatment have no other medical treatment options at this time. Lastly, it is true that the study was underenrolled (which we noted) for a variety of reasons. One goal of our study was to evaluate the efficacy of the Lille score to predict outcome in anakinra‐treated patients (which it appeared to do well). Many of the issues of concern raised by the authors related to infection, kidney injury, and so on are addressed in the publication. In summary, we can all agree that new biomarkers and new therapies are urgently needed in this very serious disease process. FUNDING INFORMATION National Institutes of Health, Grant/Award Number: 1P50AA024337, P50 AA024333, R21 AR 071046, RO1 AA028190, RO1 DK113196, RO1 GM119174, U01 AA026977, U01AA021890, U01AA021901, U01AA026938, UH3 AA026970, UO1 AA021890, UO1 AA023902, UO1 AA026933, UO1 AA026976 and UO1 AA026976‐03S1. Aimee Kross‐Desrosiers is supported by Vetrans Affairs Health Services Research & Development Service funding. CONFLICT OF INTEREST Gynogyi Szabo owns stock and consults for Zomagen Bioscience. She owns stock in Glympse and Satellite Bio. She consults for Durect Corp, Cyte, Novartis, Pandion Therapeutics, Surrozen, Terra Firma, Pfizer, Merck, and Evive.